Early increase of oxidative stress and soluble CD40L in children with hypercholesterolemia.

OBJECTIVES: The aim of the study was to analyze the behavior of oxidative stress and its interplay with CD40L, a protein that is implicated in atherosclerosis, in hypercholesterolemic children. BACKGROUND: Oxidative stress has been suggested to play a major role in premature atherosclerosis. METHODS: Forty-one children with hypercholesterolemia (mean age 9.28 +/- 0.5 years) and 40 children with normocholesterolemia (mean age 9.02 +/- 0.69 years) were matched for gender and age. Within each group, children were classified as having or not having a family history of cardiovascular disease. Serum levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, and plasma levels of soluble CD40L (sCD40L) were measured in each child. In a subgroup of children with high (n = 8) or normal (n = 8) levels of serum cholesterol, platelet p38 mitogen-activated protein (MAP) kinase phosphorylation, a protein involved in the activation of nicotinamide adenine dinucleotide phosphate oxidase, was determined. RESULTS: Children with hypercholesterolemia had higher values of 8-OHdG and sCD40L compared with control subjects (0.55 +/- 0.06 ng/ml vs. 0.21 +/- 0.02 ng/ml, p < 0.001 and 0.55 +/- 0.04 ng/ml vs. 0.19 +/- 0.03 ng/ml, p < 0.001, respectively). A significant correlation between 8-OHdG and sCD40L was observed in children with high (r = 0.676, p < 0.001) or normal (r = 0.878, p < 0.001) levels of cholesterol. Children with a family history of cardiovascular disease tended to have higher values of 8-OHdG and sCD40L, but the difference was not significant. Analysis of platelet p38 MAP kinase showed that it was phosphorylated more in children with hypercholesterolemia compared with control subjects (36.8 +/- 5.8 AU vs. 8.0 +/- 4.5 AU, p < 0.001 respectively). CONCLUSIONS: Children with hypercholesterolemia have an early increase of oxidative stress that may be responsible for up-regulation of CD40L and potentially predispose to premature atherosclerosis.     

Effects of captopril on hemodynamics and blood gases in chronic obstructive lung disease with pulmonary hypertension

The effects of Captopril, an angiotensin-converting enzyme inhibitor, on pulmonary hemodynamics and blood gases were studied in 9 patients with chronic obstructive lung disease (COLD) and pulmonary hypertension (PA-P greater than 20 mm Hg). Hemodynamic data were recorded prior to Captopril administration (50 mg per os) and for the next 60 min. Following Captopril administration, significant reductions in mean pulmonary artery pressure (PA-P) (p less than 0.05), in mean pulmonary wedge pressure (PW-P) (p less than 0.05), and in total pulmonary resistance (TPR) were noted; significant reductions in mean brachial artery pressure (BA-P) and systemic vascular resistance (SVR) were also recorded, while cardiac output, heart rate and blood gas tensions showed no significant changes. Furthermore, the higher the hypoxemia, the greater was the reduction in BA-P (p less than 0.05). We therefore feel that Captopril, when administered to COLD patients with pulmonary hypertension, may protect the pulmonary circulation from hypoxic pulmonary vasoconstriction.     

Haemophilia A: molecular insights.

Haemophilia A is the most common inherited bleeding disorder caused by defects in the F8C gene that encodes coagulation factor VIII. This X-linked recessive disorder occurs in approximately 1:5000 males. Haemophilia A is diagnosed based on normal prothrombin time, altered activated partial thromboplastin time and reduced factor VIII activity in plasma. Carrier females are usually asymptomatic and can be identified only by molecular analysis. The most frequent mutations in F8C are intron 22 and 1 inversions, which occur in approximately 50% and 5% of patients, respectively, with a severe phenotype. Large gene deletions are observed in approximately 5% of alleles from patients with severe haemophilia A. The remaining severe cases and all moderate and mild cases result from numerous point mutations and small insertions/deletions, which are de novo mutations in one-third of cases. Thus, molecular diagnosis of carrier status and prenatal diagnosis in families without intron 22 or 1 inversions is based on scanning techniques or gene sequencing. When the disease-causing mutation cannot be identified, molecular diagnosis is performed by linkage analysis of several DNA polymorphic markers linked to F8C. Given the clinical heterogeneity among haemophilic patients, many groups, including our own, have examined the relationships between prothrombotic gene variants and haemophilic phenotype to investigate whether prothrombotic gene variants modify clinical expression of the disease.     

Laparoscopic Treatment of Gallbladder and Common Bile Duct Stones: A Prospective Study

n = 2), port site infection ( n = 2), and subumbilical hematoma ( n = 1). Major morbidity was bile leakage from the cystic duct stump in two cases due to clips or transcystic duct drainage displacement, respectively. One elderly, high risk patient died after being referred for several failed attempts of endoscopic clearance; she died from cardiogenic shock 3 days after successful laparoscopic treatment. Laparoscopic CBD exploration is feasible and safe in most patients, with short-term results that compare favorably with the results of sequential ES/LC reported in the literature.     

Computed tomography of renal metastases

Since the advent of CT, secondary neoplastic lesions of the kidneys have been detected with increasing frequency. After reviewing a large series of cases of renal metastases, we have been able to classify the CT findings into seven major categories that are discussed and illustrated in this article. The differential diagnoses between metastatic disease of the kidneys and other lesions such as renal infarctions, renal lymphoma, and primary malignancies are also considered.     

Urinary mercapturic acid diastereoisomers in rats subchronically exposed to styrene and ethanol

 Styrene is stereoselectively oxidized by cytochrome P450 to its reactive metabolite, styrene oxide. The (R)- and (S)-enantiomers of styrene oxide can be conjugated with glutathione (GSH) to both (R)- and (S)-diastereoisomers of the specific mercapturic acids, N-acetyl-S-(1-phenyl-2-hydroxyethyl)-L-cysteine (M1) and N-acetyl-S-(2-phenyl-2-hydroxyethyl)-L-cysteine (M2). Several investigations have indicated different toxic potential of the (R)- and (S)-configurations of styrene oxide and its GSH- and N-acetyl-conjugates. In this study the mercapturic acid diastereoisomers were measured in the urine of rats exposed to styrene in combination with ethanol, a good inducer of styrene metabolism. Male Sprague-Dawley rats were given an isocaloric liquid diet containing ethanol (5% w/v) for 3 weeks. Starting from the 2nd week, the animals were also exposed to styrene vapours (300 ppm, 6 h/day, 5 days/week) in a dynamic exposure chamber. Both the (R)- and (S)-diastereoisomers of the M1 and M2 as well as the conventional biomarkers, mandelic acid (MA) and phenylglyoxylic acid (PGA) were measured in urinary samples. Approximately 30 and 25% reduction of the levels of brain non-protein sulfhydryls (NPS) was observed in the animals given styrene and ethanol, respectively, while the combined ethanol and styrene treatment resulted in a 60% decrease. Ethanol consumption also resulted in higher urinary levels of the M1-R, M1-S and M2 metabolites associated with increased M1-R/S ratio and higher urinary MA excretion compared to animals treated with styrene. These results suggest that the urinary mercapturic acid diastereoisomers may be used as a noninvasive tool to examine stereoselective patterns of styrene metabolism in vivo, as well as their alterations caused by ethanol. These compound-specific mercapturic acids may also be valuable indicators of styrene-induced disorders of GSH homeostasis in nonaccessible organs. Received: 19 December 1995/Accepted: 10 May 1996     

Role of vasopressin on excitatory amino acids mediated pressor responses in the periaqueductal gray area

In order to evaluate the role played by vasopressin on pressor responses elicited by stimulation of the periaqueductal gray (PAG) area by excitatory amino acids we carried out in vivo studies in genetically vasopressin deficient rats (Brattleboro). Microinjections of l-glutamic acid (glutamate, 0.6 to 60 nmol/rat) or N-methyl-d-aspartic acid (NMDA, 0.07 to 7 nmol/rat) into the PAG area of freely moving Brattleboro rats induced increases of arterial blood pressure values significantly lower than those obtained in Long Evans rats (control) (glutamate in Brattleboro rats: from +2±1 mmHg to 16±3 mmHg; glutamate in Long Evans rats: from +16±2 mmHg to +36±4 mmHg; NMDA in Brattleboro rats: from +5±2 mmHg to +34 ±8 mmHg; NMDA in Long Evans rats: from +18±7 mmHg to 80±9 mmHg; n=5). Similarly, in anaesthetized Brattleboro rats (urethane 1.2 g/kg i.p.) pressor responses to NMDA microinjections (0.7 nmol/rat) into the PAG area were significantly lower than in Long Evans rats (controls) (+15±3 mmHg vs +24±4 mmHg). In Long Evans rats NMDA injection also reversed blood pressure decrease induced by ganglionic blocker, hexamethonium and/or losartan (3 mg/kg i.v.), an AT1 receptor antagonist. In Brattleboro rats, NMDA injection did not reverse blood pressure decreases induced by hexamethonium (5 mg/kg i.v.). Moreover, hexamethonium induced blood pressure decrease was not reversed by acetylcholine injection (137 nmol/rat) into the PAG area of anaesthetized Long Evans rats, but if injected before hexamethonium, acetylcholine was able to increase blood pressure (+25±3 mmHg). Our results document: i) the importance of the PAG area in the control of cardiovascular system; ii) the involvement of excitatory amino acids in the neural control of vasopressin release; iii) the close relationship between glutamate and vasopressin in the central blood pressure regulation. Received: 1 April 1997 / Accepted: 2 February 1998